Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease
Abstract
:1. Introduction
2. Current Therapeutic Approaches Only Target Symptoms of AD
3. Therapeutic Strategies Based on Targeting Amyloid β and Tau Proteins
4. Prospect of APOE4 as a Drug Target for AD
5. Reactive Oxygen and Reactive Nitrogen Species in AD
6. Single Target Strategies in Management of AD
7. Drug Combinations as a Strategy for AD Therapy
8. Restoring Protein Homeostasis as a Novel Multifactorial Approach
9. Multiple Targets of Polyphenols against AD
9.1. Polyphenols as Antioxidants
9.2. Modulation of Protein Homeostasis and Longevity with Polyphenols
9.3. Polyphenols and Cellular Lipid Balance
9.4. Anti-inflammatory Activity of Polyphenols
9.5. Polyphenols as Anti-amyloid Agents
9.6. Polyphenols in Cognition and Synapsis
10. Future Directions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AD | Alzheimer’s Disease |
Aβ42 | β-amyloid of 42 amino acids |
Aα | Amyloid α |
NGF | Nerve Growth Factor |
FDA | Food and Drug Administration |
NMDAR | N-Methyl-D-Aspartic Receptor |
APP | Amyloid Precursor Protein |
BACE | β-Secretase |
NFT | Neurofibrillary Tangle |
NFκB | Nuclear factor kappa B |
MAPK | Mitogen-Activated Protein Kinase |
GSK3β | Glycogen Synthase Kinase - 3β |
CDK | Cyclin dependent kinase |
APOE | Apolipoprotein E |
ROS | Reactive Oxygen Species |
RNS | Reactive Nitrogen Species |
GABA | γ-amino butyric acid |
cGMP | Cyclic guanosine monophosphate |
cAMP | Cyclic adenosine monophosphate |
COX | Cyclooxygenase |
PPARγ | Peroxisome proliferator-activated receptor γ |
FAAH | Fatty acid amide hydrolase |
MAGL | Mono acyl glycerol lipase |
BDNF | Brain-derived neurotrophic factor |
NT | Neurotrophin |
Trk | Tropomyosin receptor kinase |
PI3K | Phosphatidylinositol-3-kinase |
Akt | Protein kinase B |
BBB | Blood Brain Barrier |
ECB | Encapsulated Cell Bio-delivery |
AChE | Acetylcholine esterase |
MAO | Monoamine oxidase |
UPR | Unfolded protein response |
IRE | Inositol response element |
ATF | Activating transcription factor |
PERK | Protein kinase RNA-like endoplasmic reticulum kinase |
LAMP | Lysosome associated molecular pattern |
ATP | Adenosine triphosphate |
AMPK | Adenosine monophosphate kinase |
mTOR | Mechanistic Target of Rapamycin |
NADPH | Dihydronicotinamide-adenine dinucleotide phosphate |
NOX | NADPH oxidase |
TFEB | Transcription factor EB |
SIRT1 | Sirtuin 1 |
FOXO | Fork head box like protein O |
Nrf | Nuclear factor erythroid-2 related factor |
Keap | Kelch-like ECH-associated protein 1 |
Maf | Masculoaponeurotic fibrosarcoma |
ARE | Antioxidant response element |
UDP | Uridine diphosphate |
PGC1 | PPARγ coactivator-1 |
TFAM | Transcription factor A, mitochondrial |
EGCG | Epigallocatechin-3-gallate |
ULK | Unc-51 like autophagy activating kinase |
c-JNK | c-Jun N-terminal kinase |
CLEAR | Coordinated lysosomal expression and regulation |
HDAC | Histone deacetylase |
Atg | Autophagy related |
CAMKK | Calcium/Calmodulin-dependent protein kinase kinase |
Bcl | Beclin |
ERK | Extracellular signal-regulated kinases |
HMGCoA | 3-hydroxy-3-methyl-glutaryl-Coenzyme A |
DNMT | DNA (cytosine-5)-methyltransferase |
HO | Heme oxygenase |
HSP | Heat shock protein |
TNF | Tumor necrosis factor |
IL | Interleukin |
SOD | Superoxide dismutase |
CREB | cAMP response element-binding protein |
Bax | Beclin-2- associated X |
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Polyphenol | Analytical System | EPCa/ROAb | Effects of Polyphenols at Cellular Level | Effects in Relation to AD | Reference |
---|---|---|---|---|---|
Quercetin | In vitro | NA | mTORC inhibitor | Induces autophagy, anti-amyloidogenic, inhibits proteasomal degradation, antioxidant, restores biometal distribution, antiproliferative and enhances neuronal synapsis | [4,5,6,7,8] |
ARPE 19 cells | 2 μM | TFEB activation | |||
APPswe cells | 10 μM | Inhibits Aβ fibril formation | |||
Rat neonatal cardiomyocytes | 5 μM | Inhibits all the catalytic subunits of proteasome | |||
In vitro | NA | Chelates iron | |||
In vitro | NA | Reduces ROS and RNS | |||
In silico and in vitro | NA | Inhibits acetyl choline esterase | |||
Resveratrol | Tg6799 mice | 60 mg/kg/d for 60 d/oral administration | Reduces amyloid plaque formation | Induces autophagy, increases lysosomal biogenesis, restores lipid homeostasis, increases stress resistance, regulates cell cycle, antiproliferative, anti-apoptotic, increases longevity and anti-inflammatory | [9,10,11,12,13,14] |
Primary neuronal culture | 30 μM | SIRT1 activation and NFκB inhibition | |||
Obese healthy men clinical trial | 150 mg/d for 30 d/oral administration | TFEB activation | |||
Human aortic endothelial cells | 50 μM | AMPK mediated LC3II activation | |||
Human aortic endothelial cells | 10 μM | Decreases ROS and RNS, increases SOD | |||
LNCaP cells | 20 μM | p53 regulation, PI3K/Akt/mTOR inhibition, induces FOXO transcriptional activity including cell cycle regulation and stress resistance | |||
Epigallocatechin gallate (EGCG) | Human bladder cancer cell line T24 | 20 μg/ml | Inhibits Beclin1 suppressors and PI3K/Akt/mTOR | Induces autophagy, restores lipid homeostasis, anti-amyloidogenic, increases antioxidant capacity, restores impaired autophagosomes and biometal distribution, increases cell survival | [15,16,17,18,19] |
Bovine aortic endothelial cells | 10 μM | Increases LC3II formation and activates AMPK/ULK1 | |||
HepG2 cells | 40 μM | Degrades lipid droplets through Ca2+/CAMKKB AMPK dependent mechanism | |||
In vitro | NA | Chelates zinc and copper | |||
PC12 cells (rat pheochromocytoma | 100 μg/mL | Interacts with Aβ40 and changes its conformation, inhibits lipofuscin formation | |||
Anthocyanin | Sprague–Dawley rats | 100 mg/kg/d for 28 d/oral administration | Restores calcium homeostasis and activates Nrf2 subsequently activating phase II detoxifying genes | Activates autophagy, increases expression of anti-oxidant genes, reduces ROS and increases cell survival | [20,21,22,23] |
HT22 cells and primary cultures of hippocampal neurons | 0.1 mg/mL | Induces AMPK | |||
In vitro | 0.005 mg/mL | ROS scavenging | |||
HCC cell lines PLC/PRF/5 and HepG2 cells | 0.2 mg/mL | Increase expression of Beclin1, LC3 II | |||
Kaempferol | SK-HEP-1 human hepatic cancer cell | 75 μM | Increases the levels of p-AMPK, LC3-II, Atg 5, Atg 7, Atg 12 and beclin 1, inhibits PI3K/Akt/mTOR | Reduces mitochondrial dysfunction, anti-proliferative, increases autophagy, increases unfolded protein response, reduces APOE4 fragmentation and associated toxicity | [24,25,26,27] |
BALB/c nude mice | 150 mg/kg/d for 31 d/intraperitoneal injection | Activates DNMT methyltransferase ubiquitination | |||
SCC-4, human tongue squamous cell carcinoma cell | 50 µM | Activates IRE1-JNK-CHOP signaling, downregulates ERK1/2 signaling which reduces MMP2 | |||
Hydroxytyrosol | Male db/db (C57BL/6J) mice | 10 mg/kg/d for 8 weeks/oral administration | Activates Nrf2 and SIRT1/AMPK/PGC-1, reduces protein oxidation, increases NMDAR1 and NGF mRNA expression | Enhances autophagy, increases stress resistance and longevity, antioxidant, anti-inflammatory, restores lipid homeostasis and improves cognition | [28,29,30,31,32,33] |
VECs cells | 50 μM | Activates AMPK/FOXO3a | |||
VECs cells | 10 μM | Reduces ROS | |||
VAFs from Sprague–Dawley rats | 25 μM | Increases LC3II/LC3I, Bcl1 and SIRT1 expression | |||
HepG2 and Huh7 cells | 100 μM | Inhibits PI3K/Akt/mTOR, expression of IL1β & IL6, and NFκB DNA binding | |||
Rat hepatocytes | 25 μM | Inhibits Acetyl CoA carboxylase, HMG CoA reductase, diacylglycerol acyl transferase | |||
Oleuropein aglycone | Rat ventricular myocyte | 100 μM | Increases Bcl1 and LC3II expression, TFEB nuclear localization, LAMP1 and p62 expression | Induces autophagy, increases lysosomal biogenesis and reduces oxidative damage | [33,34,35] |
Human SH-SY5Y neuroblastoma cells and rat RIN5F insulinoma cells | 50 μM | Inhibits MAOA, induces AMPK/ULK1, inhibits mTOR | |||
Rat hepatocytes | 25 μM | Inhibits acetyl CoA carboxylase, HMG CoA reductase and diacylglycerol acyl transferase | |||
Curcumin | Male Sprague–Dawley rats | 15 mg/kg/d for 4 weeks/subcutaneous injection | Activates AMPK and regulates lipid metabolism | Induces autophagy, restores lipid homeostasis, antioxidant, anti-amyloidogenic, anti-inflammatory, anti-apoptotic antiproliferative, increases lysosomal biogenesis and longevity | [36,37,38,39,40,41,42,43,44,45] |
Adult male Wistar rats | 30 mg/kg for 30 d/oral administration | Activates Nrf2, inhibits NFκB and mTOR | |||
Adult Swiss male albino mice | 80 mg/kg/d for 7 d/intraperitoneal injection | Inhibits MaoB and reduces ROS | |||
APPswe Tg2576 transgenic mice (chronic 500 ppm curcumin diet) | Blood curcumin level ~2 μM for 1 h/injection in right carotid artery | Inhibits formation of Aβ, oligomers, fibrils and plaques | |||
Tsc2+/+, Tsc2−/− MEFs and HCT116 cells | 10 μM | Activates TFEB, increases levels of LC3 and inhibits pAkt | |||
Sprague–Dawley rats’ primary cortical neurons | 10 μM | Upregulates SIRT1 and inhibits Bax | |||
APP/PS1 double transgenic mice | 160 ppm for 6 months/oral administration | Inhibits PI3K/Akt/mTOR signaling, increases LC3I/II and Beclin1 expression | |||
Myricetin | HepG2 Cells | 50 μM | Inhibits mTOR and increases LC3II expression | Induces autophagy, antiproliferative, increases stress resistance, longevity, antioxidant capacity and mitochondrial regeneration | [46,47,48] |
Adipocytes differentiated from C3H10T1/2 cells | 10 μM | Activates SIRT1/SIRT3/SIRT5 | |||
Male ICR mice | 50 mg/kg/d for 21 d/oral administration | Increases mitochondrial mass and increases PGC1α, SIRT1, TFAM, Nrf1 & FOXO1 | |||
Urolithin A | C2C12 myoblasts | 50 μM | Induces mitophagy, increases LC3I/LC3II and activates AMPK signaling | Increases mitophagy, and autophagy, antioxidant, increases lysosomal biogenesis, anti-inflammatory, anti-amyloidogenic, improves cognition and longevity | [49,50] |
Female APP/PS1 transgenic mice B6C3-Tg (APPswe, PS1dE9) 85Dbo/J and age-matched wild type mice | 300 mg/kg/d for 14 d/oral administration | Activates AMPK, decreases NFκB/MAPK/BACE1 activities and APP levels | |||
Ferulic Acid | HeLa cells and mouse primary hepatocytes | 1 mM | Increases LC3 II and inhibits mTOR | Anti-apoptotic, anti-amyloidogenic, antioxidant, anti-inflammatory and induces autophagy | [51,52,53,54] |
In vitro | NA | Inhibits Aβ aggregation and reduces ROS | |||
(APP)swe/presenilin 1(PS1)dE9 (APP/PS1) mouse model | 5.3 mg/kg/d for 6 months/oral administration | Reduces amyloid deposition and interleukin-1 beta (IL-1β) levels | |||
Acacetin | Drosophila melanogaster | 100 μM | Inhibits BACE1 | Anti-amyloidogenic, antioxidant, anti-inflammatory and induces autophagy | [55,56,57,58] |
C57BL/6J mice | ∼10 mg/kg/d for 14 d/oral administration (gavage) | Inhibits MAPK and PI3K/Akt pathways | |||
ICR mice | 100 mg/kg for 7 h/intraperitoneal injection | Increases LC3II, Atg5 and Atg7 expression, modulates TNF-α/IL-6 expression and suppresses TLR4 signaling | |||
Baicalein | SH-SY5Y human neuroblastoma cells | 12.5 μM | Increases ROS scavenging and activates Nrf2 | Anti-amyloidogenic, anti-apoptotic, antioxidant, anti-inflammatory, inhibits excitotoxicity, stimulates neurogenesis and neuronal differentiation | [59,60,61,62,63,64,65] |
In vitro | NA | Chelates iron | |||
CHO/APPwt cells | 5 μM | Induces α-secretase and inhibits Aβ formation | |||
In vitro | 30 μM | Dissociates amyloid aggregates, Aβ oligomerization and fibrillation | |||
HeLa cells | 100 μM | Inhibits NFκB activation | |||
C57BL/6J APP/PS1 mice | 80 mg/kg/d for 60 d/oral administration (drinking water) | Inhibits GSK3β mediated tau phosphorylation | |||
Sprague-Dawley male rats | 20 mg/kg 30 min before and 2/4 h after onset of ischemia/intraperitoneal injection | Induces Bcl-2/Bcl-xL associated phosphorylation | |||
Icariin | Primary cortical neurons prepared from E16-17 mouse embryos | 1.2 μM | Activates SIRT1 | Antioxidant, anti-amyloidogenic, reduces ER stress, increases synapsis and neuronal plasticity, inhibits tau hyperphosphorylation, increases cell viability, antiapoptotic and anti-inflammatory | [66,67,68,69,70,71,72,73] |
Wistar rats | 60 mg/kg/d for 3 months/oral administration | Increases SOD activity | |||
Tg2576 mouse model | 60 mg/kg/d for 3 months/oral administration | Reduces expression of BACE1 and APP | |||
Sprague-Dawley rats | 120 mg/kg/d for 28 d/oral administration | Induces PSD95, BDNF, pTrkB, pAkt, and pCREB expression | |||
SH-SY5Y cells | 1 μM | Inhibits GSK3β activation | |||
PC12 cells | 10 μM | Inhibits JNK/p38, MAPK and p53 activity | |||
HT29 and HCT116 | 20 μM | Inhibits NFκB signaling | |||
Nobiletin | Male 3XTg-AD mice | 30 mg/kg/d for 3 months/intraperitoneal injection | Reduces Aβ levels and plaque formation in brain | Anti-amyloidogenic, increases stress resistance, neuronal synapsis and plasticity, antioxidant and anti-inflammatory | [74,75,76,77] |
Male Sprague-Dawley rats | 25 mg/kg/d for 3d/intraperitoneal injection | Increases activity of Akt, CREB, BDNF and Bcl2, increases Nrf2, HO-1, SOD1 and GSH expression, reduces NFκB, MMP-9 and MDA expression | |||
Genistein | In silico and in vitro | NA | Inhibits chymotrypsin-like activity of proteasomes | Antioxidant, increases degradation of Aβ, increases apoptosis, enhances autophagy and inhibits proteasomal protein degradation | [78,79,80,81] |
LNCaP cells | 100 μM | Increases Kip1 and reduces IκBα/Bax | |||
Human dermal fibroblasts (HDFa) | 30 μM | Increases TFEB expression | |||
Human mammary gland tumor cells (MCF-7) | 0.5 μM | Enhances antioxidant gene expression | |||
Luteolin | HT-29 cells | 50 μM | Reduces ROS, NFκB signaling, Cox2 expression, blocks JAK/STAT signaling | Anti-inflammatory, antioxidant, modulates autophagy and apoptosis, increases survival | [82,83,84,85,86] |
Male Sprague-Dawley rat myocytes | 8 μM | Downregulates Bax expression, upregulates PI3k/Akt signaling and Bcl-2 expression | |||
Human HCC cell line SMMC-772 | 100 μM | Increases expression of LC3B-II, Bcl1 and caspase 8 | |||
Mangiferin | Swiss albino male rats | 15 mg/kg/d for 14 d/intraperitoneal injection | Increases ROS scavenging, activates Nrf2, inhibits NFκB signaling, increases GSH levels, decreases lipid peroxidation | Antioxidant, anti-apoptotic, chelates metals, increases stress resistance, autophagy, longevity, neuronal synapsis and plasticity | [87,88,89,90,91] |
In vitro | NA | Rescues mitochondrial respiration, chelates iron | |||
Male Swiss albino mice | 40 mg/kg/d for 21 d/oral administration | Reduces lipid peroxides and ROS/RNS induced by aluminum and restores regulation of BDNF and NGF | |||
Human astroglioma U87MG, U373MG and CRT-MG cells | 100 μM | Inhibits PI3K/Akt signaling, MAPK pathway, MMP9 gene expression |
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Dhakal, S.; Kushairi, N.; Phan, C.W.; Adhikari, B.; Sabaratnam, V.; Macreadie, I. Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease. Int. J. Mol. Sci. 2019, 20, 5090. https://doi.org/10.3390/ijms20205090
Dhakal S, Kushairi N, Phan CW, Adhikari B, Sabaratnam V, Macreadie I. Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease. International Journal of Molecular Sciences. 2019; 20(20):5090. https://doi.org/10.3390/ijms20205090
Chicago/Turabian StyleDhakal, Sudip, Naufal Kushairi, Chia Wei Phan, Benu Adhikari, Vikineswary Sabaratnam, and Ian Macreadie. 2019. "Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer’s Disease" International Journal of Molecular Sciences 20, no. 20: 5090. https://doi.org/10.3390/ijms20205090